Biol Blood Marrow Transplant 25 (2019) 18591868 Biology of Blood and Marrow Transplantation journal homepage: www.bbmt.org Lower Graft-versus-Host Disease and Relapse Risk in Post-Transplant CyclophosphamideBased Haploidentical versus Matched Sibling Donor Reduced-Intensity Conditioning Transplant for Hodgkin Lymphoma Sairah Ahmed1, Jennifer A. Kanakry2, Kwang W. Ahn3,4, Carlos Litovich3, Hisham Abdel-Azim5,6, Mahmoud Aljurf7, Vera Ulrike Bacher8, Nelli Bejanyan9, Jonathon B. Cohen10, Umar Farooq11, ~ os-Meade12, Nilanjan Ghosh13, Alex F. Herrera14, Nasheed M. Hossain15, Ephraim J. Fuchs12, Javier Bolan David Inwards , Abraham S. Kanate17, Rodrigo Martino18, Pashna N. Munshi19, Hemant Murthy20, 16 Alberto Mussetti21, Yago Nieto1, Miguel-Angel Perales22, Rizwan Romee23, Bipin N. Savani24, Sachiko Seo25, Baldeep Wirk26, Jean A. Yared27, Ana Sureda21, Timothy S. Fenske28, Mehdi Hamadani3,* 1 University of Texas, MD Anderson Cancer Center, Houston, Texas 2 National Cancer Institute, National Institutes of Health, Bethesda, Maryland 3 Center for International Blood and Marrow Transplant Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 4 Division of Biostatistics, Institute for Health and Society, Medical College of Wisconsin, Milwaukee, Wisconsin 5 Division of Hematology, Oncology and Blood & Marrow Transplantation, Children's Hospital Los Angeles, Los Angeles, California 6 University of Southern California Keck School of Medicine, Los Angeles, California 7 Department of Oncology, King Faisal Specialist Hospital Center & Research, Riyadh, Saudi Arabia 8 Department of Hematology, Inselspital, Bern University Hospital, Bern, Switzerland 9 Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida 10 Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 11 Division of Hematology, Oncology and Blood & Marrow Transplantation, University of Iowa Hospitals and Clinics, Iowa City, Iowa 12 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 13 Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Atrium Health, Charlotte, North Carolina 14 Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California 15 Department of Medicine, Division of Hematology/Oncology, Loyola University Chicago-Stritch School of Medicine, Maywood, Illinois 16 Division of Hematology, Mayo Clinic, Rochester, Minnesota 17 Osborn Hematopoietic Malignancy and Transplantation Program, West Virginia University, Morgantown, West Virginia 18 Divison of Clinical Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain 19 Georgetown University Hospital, Washington, DC 20 Division of Hematology/Oncology, University Florida College of Medicine, Gainesville, Florida 21 Hematology Department, Institut Catala  d'Oncologia-Hospitalet, Barcelona, Spain 22 Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 23 Dana Farber Cancer Institute, Boston, Massachusetts 24 Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 25 Department of Haematology and Oncology, Dokkyo Medical University, Mibu, Tochigi, Japan 26 Division of Bone Marrow Transplant, Seattle Cancer Care Alliance, Seattle, Washington 27 Blood & Marrow Transplantation Program, Division of Hematology/Oncology, Department of Medicine, Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, Maryland 28 Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin Article history: A B S T R A C T Received 26 February 2019 Classic Hodgkin lymphoma (cHL) patients with relapsed or refractory disease may benefit from allogeneic hematopoi- Accepted 20 May 2019 etic cell transplantation (allo-HCT), but many lack a matched sibling donor (MSD). Herein, we compare outcomes of 2 reduced-intensity conditioning (RIC) HCT platforms in cHL: T cellreplete related donor haploidentical (haplo) HCT Financial disclosure: See Acknowledgments on page 1867. * Correspondence and reprint requests: Mehdi Hamadani, MD, Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Suite C5500, Milwaukee, WI 53226. E-mail address: mhamadani@mcw.edu (M. Hamadani). https://doi.org/10.1016/j.bbmt.2019.05.025 1083-8791/© 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. 1860 S. Ahmed et al. / Biol Blood Marrow Transplant 25 (2019) 18591868 with a post-transplant cyclophosphamide (PTCy)-based approach versus an MSD/calcineurin inhibitor (CNI)-based Key Words: approach. The study included 596 adult patients who underwent a first RIC allo-HCT for cHL between 2008 and 2016 Hodgkin lymphoma using either a haplo-PTCy (n = 139) or MSD/CNI-based (n = 457) approach. Overall survival (OS) was the primary end- Haploidentical transplantation point. Secondary endpoints included acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD), nonrelapse Allogeneic transplantation mortality (NRM), relapse/progression, and progression-free survival (PFS). On multivariate analysis, there was no sig- Alternative donor nificant difference between haplo/PTCy and MDS/CNI-based approaches in terms of OS (hazard ratio [HR], 1.07; 95% confidence interval [CI], .79 to 1.45; P = .66) or PFS (HR, .86; 95% CI, .68 to 1.10; P = .22). Haplo/PTCy was associated with a significantly higher risk of grades II to IV aGVHD (odds ratio [OR], 1.73, 95% CI, 1.16 to 2.59; P = .007), but the risk of grades III to IV aGVHD was not significantly different between the 2 cohorts (OR, .61; 95% CI, .29 to 1.27; P = .19). The haplo/PTCy platform provided a significant reduction in cGVHD risk (HR, .45; 95% CI, .32 to .64; P < .001), and a signifi- cant reduction in relapse risk (HR, .74; 95% CI, .56 to .97; P = .03). There was a statistically nonsignificant trend toward higher NRM with a haplo/PTCy approach (HR, 1.65; 95% CI, .99 to 2.77; P = .06). Haplo/PTCy-based approaches are associated with lower incidences of cGVHD and relapse, with PFS and OS outcomes comparable with MSD/CNI-based approaches. There was a leaning toward higher NRM with a haplo/PTCy-based platform. These data show that haplo/PTCy allo-HCT in cHL results in survival comparable with MSD/CNI-based allo-HCT. © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. INTRODUCTION consecutively; patients are followed longitudinally, and compliance is monitored by on-site audits. Computerized checks for discrepancies, physicians' review of Classic Hodgkin lymphoma (cHL) patients with relapsed/ submitted data, and on-site audits of participating centers ensure data quality. refractory disease may benefit from allogeneic hematopoietic The CIBMTR collects data at 2 levels, transplant essential data in all patients and cell transplantation (allo-HCT). cHL patients who relapse after more comprehensive data (Comprehensive Report Forms) in a subset of patients an autologous HCT have poor outcomes, with a 5-year overall selected by a weighted randomization scheme. Observational studies conducted survival (OS) of »30% [1,2]. Although in theory myeloablative by the CIBMTR are performed in compliance with all applicable federal regula- tions pertaining to the protection of human research participants. Protected conditioning could improve disease control going into allo- health information used in the performance of such research is collected and HCT, these higher intensity approaches in allo-HCT for cHL maintained in CIBMTR’s capacity as a Public Health Authority under the HIPAA have generally been associated with higher rates of nonrelapse Privacy Rule. The Institutional Review Boards of the Medical College of Wiscon- mortality (NRM) [35]. Reduced-intensity conditioning (RIC) sin and the National Marrow Donor Program approved this study. regimens have extended the use of allo-HCT to those who Patients relapse after autologous HCT, older patients, and those with Included in this analysis were adult (18 years) cHL patients undergoing significant comorbidities [68]. In a disease for which immu- their first nonmyeloablative or RIC (NMA/RIC) allo-HCT between 2008 and notherapy has shown great promise, the application of cellular 2016. This was a comparison of 2 HCT approaches, with eligible patients immunotherapy in the form of allo-HCT will likely remain a either receiving a T cellreplete related donor PTCy-based haplo graft (haplo/ PTCy-based) (§ CNI and mycophenolate mofetil) or MSD grafts with CNI- critical component of cHL therapeutics for the foreseeable based GVHD prophylaxis (MSD/CNI-based). MSD recipients could have future. Currently, there remains an ongoing risk of relapse in received antithymocyte globulin (ATG) or alemtuzumab. Patients receiving patients treated with programmed cell death protein 1 (PD-1) ex vivo graft manipulation were not included. blockade as monotherapy, and there are no conclusive data that such immunotherapy is curative for most relapsed/refrac- Definitions and Study Endpoints tory cHL. In addition, there are concerns for increased toxicity The intensity of allo-HCT conditioning regimens was categorized as NMA/ RIC using consensus criteria [14]. Disease response at the time of HCT was with allo-HCT in those treated with PD-1 inhibitors, with most determined using the International Working Group criteria in use during the patients who will go on to allo-HCT in the future likely to have era of this analysis [15]. The primary endpoint was OS; death from any cause exposure to such agents. Thus, comparing outcomes across dif- was considered an event, and surviving patients were censored at last follow- ferent RIC HCT approaches will serve to better inform how to up. Secondary outcomes included NRM, progression/relapse, and PFS. NRM was defined as death without evidence of lymphoma progression/relapse; maximize the curative potential of allo-HCT while also assess- relapse was considered a competing risk. Progression/relapse was defined as ing the impact of NRM and graft-versus-host disease (GVHD). progressive lymphoma after HCT or lymphoma recurrence after a complete In a significant proportion of patients requiring an allo-HCT, remission; NRM was considered a competing risk. For PFS, a patient was con- a conventional matched donor is not available, and several sidered a treatment failure at time of progression/relapse or death from any cause. Patients alive without evidence of disease relapse or progression were reports now show that T cellreplete related donor haploidenti- censored at last follow-up. Acute GVHD (aGVHD) and cGVHD were graded cal (haplo) HCT with post-transplant cyclophosphamide (PTCy) using established clinical criteria [16,17]. Probabilities of PFS and OS were cal- is a suitable option for patients with relapsed/refractory cHL culated using the Kaplan-Meier estimates. Neutrophil recovery was defined as with similar survival outcomes and lower rates of chronic the first of 3 successive days with an absolute neutrophil count  500/mL after GVHD (cGVHD) compared with matched sibling donors (MSDs) post-transplant nadir. Platelet recovery was considered to have occurred on the first of 3 consecutive days with a platelet count of 20,000/mL or higher in and matched unrelated donors (MUDs) [5,912]. Intriguingly, the absence of platelet transfusion for 7 consecutive days. For neutrophil and some small studies have suggested that haplo HCT may be asso- platelet recovery, death without the event was considered a competing risk. ciated with lower risk of relapse and improved progression-free survival (PFS) when compared with MSD HCT [5,13]. Statistical Analysis In this study we used a large registry dataset to examine the The haplo/PTCy cohort was compared against the MSD/CNI cohort. Cumulative incidences of hematopoietic recovery, GVHD, relapse, and NRM outcomes of 2 RIC platforms for HCT: the haplo PTCy-based were calculated to accommodate for competing risks. Associations among approach compared with MSD/calcineurin inhibitor (CNI)- patient-, disease-, and transplant-related variables and outcomes of interest based approach in patients with cHL. were evaluated using Cox proportional hazards regression for cGVHD, relapse, NRM, PFS, and OS and logistic regression for aGVHD. Forward step- METHODS wise selection was used to identify covariates that influenced outcomes. Data Source Covariates with a P < .05 were considered significant. The proportional haz- The Center for International Blood and Marrow Transplant Research ards assumption for Cox regression was tested by adding a time-dependent (CIBMTR) is a working group of more than 500 transplant centers worldwide covariate for each risk factor and each outcome. Interactions between the that contribute detailed data on HCT to a statistical center at the Medical College main effect and significant covariates were examined. The center effect was of Wisconsin. Participating centers are required to report all transplants tested using the score test for cGVHD, relapse, NRM, PFS, and OS and the S. Ahmed et al. / Biol Blood Marrow Transplant 25 (2019) 18591868 1861 generalized linear mixed model for aGVHD [18]. Results are expressed as Table 1 odds ratio (OR) for aGVHD and hazard ratio (HR) for cGVHD, relapse, NRM, Baseline Characteristics of NMA/RIC MSD or Haplo Donor Patients with HL PFS, and OS. The variables considered in multivariate analysis are shown in Registered to the CIBMTR from 2008 to 2016 Supplementary Table 1. All statistical analyses were performed using SAS ver- sion 9.4 (SAS Institute, Cary, NC). MSD (n = 457) Haplo P Donor (n = 139) RESULTS Baseline Characteristics Number of centers 131 44 Five hundred ninety-six adult cHL patients undergoing Median patient age, yr (range) 33 (18-66) 33 (19-69) .92 their first NMA/RIC allo-HCT between 2008 and 2016 and Male gender 257 (56) 81 (58) .67 reported to the CIBMTR were included. Among these, 139 Patient race <.001 received a RIC haplo/PTCy-based approach and 457 a RIC MSD/ White 371 (81) 102 (73) CNI-based approach. A higher proportion of recipients in the African American 23 (5) 27 (19) haplo/PTCy group received bone marrow as a graft source (70% Other* 61 (13) 9 (6) versus 4%) and were of African American ethnicity (19% versus 5%). A higher proportion of the MSD/CNI cohort received a Missing 2 (<1) 1 (<1) prior autologous HCT compared with the haplo/PTCy cohort Karnofsky performance 343 (75) 103 (74) .63 score  90 (84% versus 73%). Fourteen percent of the MSD/CNI group Missing 15 (3) 7 (5) received ATG or alemtuzumab compared with less than 1% in the haplo/PTCy group. Baseline patient-, disease-, and trans- HCT-CI .01 plant-related characteristics are shown in Table 1. 0 194 (42) 44 (32) 1-2 101 (22) 45 (32) Hematopoietic Recovery 3 133 (29) 46 (33) The day 28 cumulative incidence of neutrophil recovery for Missing 29 (6) 4 (3) the MSD/CNI platform patients was 98% (95% confidence inter- Previous autologous HCT 382 (84) 102 (73) .007 val [CI], 96 to 99) compared with 96% (95% CI, 92 to 98) for the Median time from diagnosis to 34 (4-338) 32 (8-236) .02 transplant, mo (range) haplo/PTCy platform (P = .25). The day 100 cumulative incidence of platelet recovery in the same order was 97% (95% CI, 95 to Remission at HCT .72 98) and 91% (95% CI, 85 to 95; P = .04) (Table 2), respectively. Complete remission 178 (39) 45 (32) Median days from HCT to neutrophil and platelet recovery for Partial remission 195 (43) 65 (47) MSD patients was 14 (range, 3 to 132) and 17 (range, 8 to 89), Resistant disease 74 (16) 26 (19) respectively, compared with 17 (range, 5 to 64) and 26 (range, Untreated relapse 6 (1) 2 (1) 11 to 103) for haplo patients, respectively. (P < .001; Table 2). Unknown 4 (<1) 1 (<1) Conditioning regimensy <.001 Graft-versus-Host Disease Flu/Mel 187 (41) 7 (5) On univariable analysis the day 180 cumulative incidence of Flu/Cy/TBI 21 (5) 122 (88) grades II to IV aGVHD after haplo/PTCy was higher at 45% (95% Others 249 (54) 10 (7) CI, 37 to 53) compared 30% in the MSD/CNI cohort (95% CI, 26 Conditioning intensity <.001 to 35; P = .003) (Table 2). The cumulative incidence of grades III NMA 137 (30) 125 (90) to IV aGVHD was not significantly different between the 2 RIC 320 (70) 14 (10) groups: 7% (95% CI, 3 to 12) and 11% (95% CI, 8 to 14; P = .14). TBI dose <.001 Multivariable analysis showed that the risk of grades II to IV 200 cGy 60 (13) 123 (88) aGVHD after haplo/PTCy was significantly higher (OR, 1.73; > 200 cGy 18 (4) 1 (<1) 95% CI, 1.16 to 2.59; P = .01) (Table 3); however, the risk of No TBI given 379 (82) 15 (11) grades III to IV aGVHD was not significantly different between Graft type <.001 the 2 groups (OR, .61; 95% CI, .29 to 1.27; P = .19) Other varia- Bone marrow 18 (4) 97 (70) bles predictive of aGVHD risk are shown in Table 3. Peripheral blood 439 (96) 42 (30) The 1-year cumulative incidence of cGVHD was significantly GVHD prophylaxis <.001 higher in the MSD/CNI platform compared with the haplo/PTCy platform at 46% (95% CI, 41 to 51) versus 23% (95% CI, 16 to 31; Post-CY § other(s) 0 139z P < .001) (Table 2 and Figure 1A). Accordingly, extensive cGVHD CNI + MMF based 142 (31) 0 was also higher in the MSD/CNI cohort compared with haplo/ CNI + MTX based 219 (48) 0 PTCy at both 1 and 3 years (Table 2). Multivariable analysis con- CNI § other(s) 96 (21) 0 firmed a lower risk of cGVHD for the haplo/PTCy platform (HR, (except MMF, MTX, PTCy) .45; 95% CI, .32 to .64; P < .001) (Table 3). ATG or alemtuzumab use 66 (14) 1 (<1) <.001 Donorrecipient gender .090 Nonrelapse Mortality Female ! male 111 (24) 38 (27) The cumulative incidence of NRM at 1 year in the haplo/ Others 346 (76) 101 (73) PTCy group was 11% (95% CI, 6 to 17) compared with 6% (95% CMV status D+/R .025 CI, 4 to 8) in the MSD/CNI group (P = .07) (Table 2 and +/ 65 (14) 29 (21) Figure 1B). On multivariable analysis, there was a trend toward Other 397 (83) 109 (79) a higher risk of NRM with the haplo/PTCy approach (HR, 1.65; Missing 13 (3) 1 (<1) 95% CI, .99 to 2.77; P = .06) (Table 3); however, this did not Year of transplant .001 attain statistical significance. Other variables independently 2008-2010 162 (35) 38 (27) associated with NRM risk were age  50 years (HR, 3.55; 95% (continued) 1862 S. Ahmed et al. / Biol Blood Marrow Transplant 25 (2019) 18591868 Table 1 (Continued) Progression-Free Survival MSD (n = 457) Haplo P PFS was not significantly different between the 2 groups Donor on univariate analysis, with 1-year and 3-year PFS in the (n = 139) MSD/CNI group of 53% (95% CI, 48 to 57) and 34% (95% CI, 30 2011-2013 187 (41) 40 (29) to 39), respectively, whereas the haplo/PTCy group had 2014-2016 108 (24) 61 (44) 1-year and 3-year PFS of 57% (95% CI, 49 to 65) and 38% (95% Median follow-up of 52 (2-101) 37 (5-109) CI, 29 to 47), respectively (Table 2, Figure 1D). Similarly, on survivors, mo (range) multivariable analysis there was no significant difference Values are n (%) unless otherwise defined. CMV indicates cytomegalovirus; Flu, between the 2 groups (Table 3). Factors impacting PFS were fludarabine; HCT-CI, HCT-specific comorbidity index; Mel, melphalan; MMF, performance status and disease status at time of transplant, mycophenolate mofetil; MTX, methotrexate; TBI, total body irradiation. as shown in Table 3. * Other: MSD: 18 Asian; 12 Hispanic, race NOS; 2 Native Pacific Islander; 2 Native American unspecified; Race not reported: 4 USA; 1 UK; 2 France; 9 Saudi Arabia; 1 Sweden; 6 Australia; 1 Brazil; 3 Canada. Haplo: 6 Asian; 2 His- panic, race NOS; 1 race NOS, Canada. Overall Survival y Details of conditioning regimens are given in Supplementary Table 2. The median follow-up for surviving patients was 37 months z GVHD prophylaxis: haplo donor: 133 CNI + MMF + Cytoxan; 2 CNI + Cytoxan; (range, 5 to 109) for the haplo/PTCy cohort and 52 months 2 Cytoxan alone; 1 MMF + Cytoxan; 1 CNI + MTX+ Cytoxan. (range, 2 to 101) for the MSD/CNI recipients. There was no sig- nificant difference in OS between the 2 platforms at either 1 or CI, 1.81 to 6.95; P < .001) and HCT-specific comorbidity index 3 years. MSD/CNI OS at 1 and 3 years was 84% (95% CI, 80 to of 1 to 2 relative to 3 (HR, .39; P = .01) (Table 3). 87) and 63% (95% CI, 58 to 67), respectively, whereas haplo/ PTCy OS at 1 and 3 years was 78% (95% CI, 71 to 85) and 63% Relapse/Progression (95% CI, 54 to 71), respectively (Table 2, Figure 1E). These The 1-year cumulative incidence of relapse was signifi- results were confirmed in multivariable analysis (Table 3). cantly higher in the MSD/CNI group at 42% (95% CI, 37 to 46) Other predictors of worse OS were age  50 years, poor perfor- compared with 32% (95% CI, 24 to 40) in the haplo/PTCy group mance status, and cHL not in complete remission at the time of (P = .04) (Table 2, Figure 1C). In multivariable analysis, haplo- allo-HCT, as shown in Table 3. Postrelapse survival (clock start- HCT was associated with a significantly reduced risk of relapse ing at relapse post-HCT) for MSD/CNI versus haplo/PTCy (HR, .74; 95% CI, .56 to .97; P = .03). Additional factors predic- patients was not significantly different (at 3 years, 42% versus tive of relapse/progression risk included performance status 44%; P = .78, respectively). No center effect was found for any and disease status, as shown in Table 3. outcomes. Table 2 Univariate Outcomes MSD (n = 457) Haplo Donor (n = 139) Outcomes No. Assessed Probability (95% CI) (%) No. Assessed Probability (95% CI) (%) P Neutrophil recovery 449 137 28 days 98 (96-99) 96 (92-98) .25 Median time from HCT to neutrophil engraftment, days (range) 14 (3-132) 17 (5-64) <.001 Platelet recovery 415 108 100 day 97 (95-98) 91 (85-95) .04 Median time from HCT to platelet recovery, days (range) 17 (8-89) 26 (11-103) <.001 Grades II to IV aGVHD 447 136 180 days 30 (26-35) 45 (37-53) .003 Grades III to IV aGVHD 420 127 180 days 11 (8-14) 7 (3-12) .14 cGVHD 444 133 1 yr 46 (41-51) 23 (16-31) <.001 3 yr 56 (51-61) 28 (21-36) <.001 Extensive cGVHD 434 132 1 yr 38 (34-43) 16 (10-23) <.001 3 yr 45 (40-50) 18 (12-26) <.001 NRM 457 139 1 yr 6 (4-8) 11 (6-17) .07 3 yr 10 (7-13) 14 (9-21) .19 Relapse/progression 457 139 1 yr 42 (37-46) 32 (24-40) .04 3 yr 56 (51-61) 48 (39-57) .14 PFS 457 139 1 yr 53 (48-57) 57 (49-65) .35 3 yr 34 (30-39) 38 (29-47) .53 OS 457 139 1 yr 84 (80-87) 78 (71-85) .14 3 yr 63 (58-67) 63 (54-71) .99 S. Ahmed et al. / Biol Blood Marrow Transplant 25 (2019) 18591868 1863 Table 3 Multivariate Analysis No. of Cases HR HR Lower CL HR Upper CL P Overall P aGVHD grades II-IV MSD 447 1.00* .01 Haplo donor 136 1.73* 1.16 2.59 .01 HCT-CI 0 232 1.00 .01 1-2 142 1.47 .95 2.28 .08 3+ 176 1.09 .72 1.66 .68 Missing 33 .14 .03 .61 .01 aGVHD grades III-IV MSD 420 1.00* .19 Haplo donor 127 .61* .29 1.27 cGVHD MSD 445 1.00 <.001 Haplo donor 133 .45 .32 .64 <.001 KPS 90% 433 1.00 .05 <90% 123 1.36 1.03 1.79 .03 Missing 22 .70 .34 1.41 .32 Relapse MSD 457 1.00 .03 Haplo donor 139 .74 .56 .97 .03 KPS 90% 446 1.00 .001 <90% 128 1.53 1.19 1.97 .001 Missing 22 1.08 .61 1.89 .80 Disease status CR 223 1.00 <.001 PR 260 2.06 1.58 2.69 <.001 Resistant 100 2.77 2.01 3.82 <.001 Untreated/missing 13 2.34 1.08 5.07 .03 NRM MSD 457 1.00 .06 Haplo donor 139 1.65 .99 2.77 .06 Age, yr 18-29 238 1.00 .001 30-39 188 1.59 .82 3.07 .17 40-49 94 2.13 1.01 4.49 .05  50 76 3.55 1.81 6.95 <.001 HCT-CI 0 238 1.00 .05 1-2 146 .60 .29 1.24 .17 3+ 179 1.56 .90 2.70 .12 Missing 33 1.49 .51 4.31 .47 Contrast 1-2 vs. 3 .39 .19 .78 .01 PFS MSD 457 1.00 .22 Haplo donor 139 .86 .68 1.10 .22 KPS 90% 446 1.00 <.001 <90% 128 1.57 1.25 1.98 <.001 Missing 22 .93 .54 1.60 .80 Disease status CR 223 1.00 <.001 PR 260 1.83 1.45 2.32 <.001 Resistant 100 2.49 1.87 3.32 <.001 Untreated/missing 13 2.35 1.19 4.66 .01 (continued) 1864 S. Ahmed et al. / Biol Blood Marrow Transplant 25 (2019) 18591868 Table 3 (Continued) No. of Cases HR HR Lower CL HR Upper CL P Overall P OS MSD 457 1.00 .66 Haplo donor 139 1.07 .79 1.45 .66 Age, yr 18-29 238 1.00 .03 30-39 188 .94 .69 1.30 .72 40-49 94 1.23 .85 1.78 .27 50 76 1.64 1.13 2.39 .01 KPS 90 446 1.00 .001 <90 128 1.63 1.22 2.17 <.001 Missing 22 1.13 .61 2.11 .70 Disease status CR 223 1.00 <.001 PR 260 1.69 1.24 2.31 <.001 Resistant 100 2.54 1.76 3.65 <.001 Untreated/missing 13 1.12 .40 3.11 .83 CL indicates confidence limit; CR, complete remission; KPS, Karnofsky performance score; PR, partial remission. * Represent OR. Multivariable Analysis with ATG/Alemtuzumab Patients results of this multivariate model were concordant with the Excluded overall study population (Table 3). Sixty-six (14%) MSD cohort patients received ATG or alem- tuzumab as part of their conditioning regimen. Because ATG/ Subgroup Analysis of Patients Receiving Peripheral Blood alemtuzumab administration can influence risk of GVHD, Grafts relapse, and NRM, we repeated the multivariate analysis after Forty-two patients who had a haplo donor received a excluding these patients. As shown in Supplementary Table 3, peripheral blood stem cell graft source and PTCy. When Figure 1. (A) Cumulative incidence of cGVHD in recipients of MSD and haplo donor (HAPLO) transplantations (overall P < .001). (B) Cumulative incidence of NRM in recipients of MSD and haplo transplants (overall P = .02). (C) Cumulative incidence of relapse and/or progression in recipients of MSD and haplo transplants (overall P = .05). (D) Kaplan-Meier estimate of PFS in recipients of MSD and haplo transplants (overall P = .51). (E) Kaplan-Meier estimate of OS in recipients of MSD and haplo transplants (overall P = .26). S. Ahmed et al. / Biol Blood Marrow Transplant 25 (2019) 18591868 1865 Table 4 Subgroup Analysis of Patients Receiving Peripheral Blood as Graft Type Outcomes MSD Haplo Donor (n = 439) (n = 42) No. Assessed Probability (95% CI)(%) No. Assessed Probability (95% CI)(%) P Grades III to IV a GVHD 404 40 .21 6 mo 11 (8-15) 5 (0-14) .09 cGVHD 427 39 .16 1 yr 46 (41-51) 35 (20-50) .15 2 yr 54 (49-59) 42 (26-59) .18 3 yr 56 (51-61) 42 (26-59) .11 NRM 439 42 <.001 1 yr 6 (4-8) 22 (11-35) .02 2 yr 8 (5-10) 22 (11-35) .03 3 yr 10 (7-13) 22 (11-35) .07 Relapse/progression 439 42 .16 1 yr 42 (37-47) 26 (14-41) .03 2 yr 53 (48-58) 45 (28-62) .40 3 yr 57 (52-61) 45 (28-62) .21 PFS 439 42 .51 1 yr 52 (47-57) 52 (37-67) 1.00 2 yr 40 (35-44) 33 (18-51) .48 3 yr 34 (29-39) 33 (18-51) .97 OS 439 42 .02 1 yr 84 (80-87) 68 (54-82) .04 2 yr 72 (68-77) 57 (40-73) .08 3 yr 62 (57-67) 49 (30-69) .23 comparing their outcomes with the MSD/CNI cohort (receiving DISCUSSION peripheral blood stem cells) there was no difference in the Donor selection for allo-HCT is based on many factors inclu- incidence of aGVHD, cGVHD, or PFS. Similar to the overall anal- sive of donor availability, HLA-compatibility, and importantly ysis, NRM was higher in the haplo/PTCy group, whereas the outcomes associated with transplant, specifically risk of severe 1-year cumulative incidence of relapse was also comparable GVHD, relapse, and NRM. In this large registry-based study, we with the overall analysis, with the MSD/CNI group at 42% (95% analyzed specifically 2 distinct platforms of donor type and CI, 37 to 47) compared with 26% (95% CI, 14 to 41) in the GVHD prophylaxis: MSD grafts with CNI-based prophylaxis haplo/PTCy group (P = .03). Corresponding to the main analysis, compared with haplo grafts with PTCy-based prophylaxis. The MSD/CNI OS at 3 years was 62% (95% CI, 57 to 67), whereas main findings of our study are as follows: (1) OS and PFS were haplo/PTCy was 49% (95% CI, 30 to 69; P = .23). Details of the similar for the 2 platforms, (2) the risk of cGVHD was signifi- subgroup analysis are listed in Table 4. cantly lower in recipients of haplo/PTCy-based approaches, (3) a lower incidence of relapse was observed for patients who received a haplo/PTCy-based platform, and (4) there was a Outcomes of Transplant According to Remission Status at nonsignificant trend toward higher NRM with haplo/PTCy- HCT based allo-HCT, seemingly related to higher fatal infectious At the time of transplant 223 patients were in complete complications. This analysis demonstrates that haplo/PTCy remission, 260 were in a partial remission, and 100 were allo-HCT provides similar survival outcomes to MSD/CNI allo- deemed to have resistant disease. The NRM between these HCT across multiple centers with a meaningful decrease in the groups was not different however; not surprisingly, those who risk of cGVHD and relapse. were in a complete remission had a statistically significant Presently, several studies are reporting the comparison of lower rate of relapse and superior PFS and OS when compared haplo HCT with conventional MSD or MUD HCT. Our study is with the partial remission and resistant disease groups. Details the largest analysis to focus solely on the comparison of an of relapse, PFS, and OS based on remission status are found in MSD/CNI platform versus a haplo/PTCy-based approach to Table 5. ascertain the risk-to-benefit profile of a haplo graft relative to the historical gold standard donor option (ie, HLA-identical Causes of Death sibling). Relapse was the leading cause of death for both groups, The European Society for Blood and Marrow Transplanta- affecting 110 (58%) MSD/CNI-based recipients and 24 (41%) tion published their registry analysis [5] comparing cHL haplo/PTCy-based recipients. The next most common cause of patients who received PTCy-based haplo HCT(n = 98) with out- death, after primary disease, in the haplo/PTCy group was comes of patients who received MSD (n = 338) or MUD infections, 20% compared with 9% in the MSD/CNI group. (n = 273) HCT and reported a 1-year NRM of 13%, 21%, and 17% GVHD was the main cause of death in 6% of the MSD/CNI group after alloHCT in MSD, MUD, and haplo transplants, respec- and in 2% of the haplo/PTCy group. Detailed information about tively, with a difference seen in the NRM risk between the causes of death is shown in Supplementary Table 4. MSD and MUD groups. Similarly, Gauthier et al. [19] 1866 S. Ahmed et al. / Biol Blood Marrow Transplant 25 (2019) 18591868 Table 5 Univariate Outcomes by Remission Status at HCT CR (n = 223) PR (n = 260) Resistant (n = 100) Outcomes No. Assessed Probability No. Assessed Probability No. Assessed Probability P (95% CI)(%) (95% CI)(%) (95% CI)(%) NRM 223 260 100 .76 1 yr 7 (4-10) 6 (3-9) 9 (4-16) .58 2 yr 8 (5-12) 8 (5-12) 10 (5-17) .78 3 yr 12 (7-17) 10 (6-14) 10 (5-17) .86 Relapse/progression 223 260 100 <.001 1 yr 24 (18-30) 46 (40-52) 58 (48-67) <.001 2 yr 33 (27-40) 57 (51-63) 66 (56-75) <.001 3 yr 37 (31-44) 61 (55-67) 69 (60-78) <.001 PFS 223 260 100 <.001 1 yr 70 (63-75) 48 (42-55) 33 (24-43) <.001 2 yr 59 (52-66) 35 (29-41) 24 (16-33) <.001 3 yr 51 (44-58) 29 (23-35) 20 (13-29) <.001 OS 223 260 100 <.001 1 yr 90 (85-93) 82 (77-86) 68 (59-77) <.001 2 yr 83 (78-88) 68 (62-74) 56 (46-66) <.001 3 yr 76 (69-82) 59 (52-65) 44 (33-54) <.001 retrospectively compared MSD (n = 90) and haplo (n = 61) HLA-identical donor HCT. Globally, despite the curative possi- recipients of NMA/RIC allo-HCT for cHL and reported a 2-year bility of allo-HCT, the relapse rate remains disappointingly NRM of 9% and 12% for haplo and MSD HCT, respectively. Mari- high; therefore, studies evaluating post-transplant mainte- otti et al. [2] compared outcomes between HLA-identical nance and consolidation are needed to address this important donors (MSD, 29; MUD, 5) and haplo (n = 30) donors for cHL unmet need for this population. patients who relapsed after an autologous transplant, with a Despite a higher risk of grades II to IV aGVHD with the 1-year NRM rate of 17%, with a tendency toward higher NRM haplo/PTCy platform in our study, the risk of severe (grades III after haplo relative to HLA-identical donors (26% versus 9% to IV) aGVHD was not higher with this approach, whereas the P = .09). Death was due mainly to cHL progression in the HLA- risk of cGVHD was significantly lower (Table 3). The higher identical donor recipients (12 versus 4), whereas more patients rate of grade II aGVHD in the haplo/PTCy cohort is line with died of complications after haplo-HCT (9 versus 6). Our study results reported by European Society for Blood and Marrow found a trend toward higher NRM with haplo/PTCy, possibly Transplantation recently, and this mirrors other data support- due to increased rate of fatal infections. Although no difference ing that PTCy appears to be effective at preventing grades III to was observed in neutrophil engraftment between the 2 IV aGVHD but is associated with grade II aGVHD in one-third approaches, we do not have access to kinetics of immune to one-half of patients [5]. A higher proportion of patients in reconstitution in the CIBMTR registry. There was also an the MSD cohort received ATG/alemtuzumab, which could cer- increase in organ failure in the haplo/PTCy group (n = 7; 12%) tainly generate the finding of decreased aGVHD; however, it is versus the MSD/CNI group (n = 14; 7%). It is also important to interesting that in the separate multivariate analysis with ATG/ highlight that the 1-year NRM of only 6% in the MSD/CNI group alemtuzumab excluded, the MSD arm continued to have a in our study is lower than historically reported rates at 1 year lower rate of aGVHD. The higher risk of cGVHD for the MSD/ (»10% to 15%) for such patients [5,912], whereas the NRM CNI platform was seen on both univariate and multivariable rates of haplo/PTCy (1 year, 11%) are consistent with recently analyses. GVHD-free relapse-free survival was an endpoint we published data [5]. Given the time period of the current study, were not able to analyze given that systemic immunosuppres- it contained cHL patients included in the 2016 CIBMTR [11,12] sion requiring cGVHD (a defined event for GVHD-free relapse- analyses of lymphoma patients who received either a haplo free survival) is not captured in our registry. Moreover, the donor or MSD between 2008 and 2013. However, there is no striking difference in cGVHD seen across the 2 groups in our overlap between patients who received in vivo T cell depletion analysis (HR, .45) essentially means that evaluation of GVHD- or the subsequent years of transplant. free relapse-free survival will show a significant difference in Relapse was the primary cause of death after allo-HCT for similar direction and serve as a surrogate for cGVHD incidence cHL patients in our and other studies. In the retrospective difference. The distinct contrast between the rates of cGVHD study by Burroughs et al. [13], 90 patients with cHL were could be related to the use of PTCy in the haplo group; how- treated with a NMA conditioning regimen followed by allo- ever, we cannot discount that the graft source overwhelmingly HCT from MSDs (n = 38), MUDs (n = 24), or haplo donors was bone marrow, which has been proven to decrease the risk (n = 28), and relapse was lowest among haplo recipients. of cGVHD across disease states and conditioning regimens Gauthier et al. [19] did not find any difference in cumulative [20]. The subgroup analysis of patients receiving peripheral incidence of relapse between haplo and MSD groups. In the blood stem cell grafts would support the latter argument current analysis, our findings reveal a lower relapse rate for given that the differences in aGVHD and cGVHD are not seen; patients receiving a haplo/PTCy-based HCT compared with however, the numbers are small, and firm conclusions cannot MSD/CNI-based HCT, which is analogous with the findings of be drawn. Recent data suggest that patients with exposure to Mariotti et al. [5], who also reported a 3-year cumulative inci- checkpoint inhibitors both before and after allo-HCT may have dence of disease relapse of 13% for haplo HCT versus 62% for an increased risk of aGVHD [2123]. Consensus guidelines by S. Ahmed et al. / Biol Blood Marrow Transplant 25 (2019) 18591868 1867 Herbaux et al. [24] highlight that there is no unanimity regard- Administration; 2 grants (N00014-17-1-2388 and N00014-16- ing optimal transplant strategy for patients previously treated 1-2020) from the Office of Naval Research; and grants from with checkpoint inhibitors; however, there is agreement in *Actinium Pharmaceuticals, Inc.; *Amgen, Inc.; *Amneal Bio- that the goal should be to reduce the risk of GVHD and veno- sciences; *Angiocrine Bioscience, Inc.; Anonymous donation to occlusive disease. Furthermore, the recommendation is to the Medical College of Wisconsin; Astellas Pharma US; Atara preferentially use a bone marrow graft and PTCy for GVHD pro- Biotherapeutics, Inc.; Be the Match Foundation; *bluebird bio, phylaxis for those who have received prior checkpoint inhibi- Inc.; *Bristol Myers Squibb Oncology; *Celgene Corporation; tors in an effort to decrease the risk of GVHD. In the CIBMTR Cerus Corporation; *Chimerix, Inc.; Fred Hutchinson Cancer registry, detailed information about pretransplant treatments is Research Center; Gamida Cell Ltd.; Gilead Sciences, Inc.; Histo- available only for patients reported at the Comprehensive Genetics, Inc.; Immucor; *Incyte Corporation; Janssen Scientific Report Forms level. Among the 80 subjects with available Com- Affairs, LLC; *Jazz Pharmaceuticals, Inc.; Juno Therapeutics; prehensive Report Forms data (MSD, 47; haplo, 33) in the Karyopharm Therapeutics, Inc.; Kite Pharma, Inc.; Medac, current study, only 1 MSD and 5 haplo patients had prior check- GmbH; MedImmune; The Medical College of Wisconsin; point inhibitor exposure. An ongoing prospective observational *Merck & Co, Inc.; *Mesoblast; MesoScale Diagnostics, Inc.; Mil- CIBMTR study will be evaluating the impact of prior checkpoint lennium, the Takeda Oncology Co.; *Miltenyi Biotec, Inc.; inhibitor exposure in cHL patients undergoing allo-HCT. National Marrow Donor Program; *Neovii Biotech NA, Inc.; Targeted immunotherapy approaches can achieve high Novartis Pharmaceuticals Corporation; Otsuka Pharmaceutical rates of response in relapsed/refractory cHL, including after Co, Ltd.  Japan; PCORI; *Pfizer, Inc; *Pharmacyclics, LLC; relapse from autologous HCT [25,26]. In current practice, allo- PIRCHE AG; *Sanofi Genzyme; *Seattle Genetics; Shire; Spec- HCT is generally reserved for cHL with both a prior autologous trum Pharmaceuticals, Inc.; St. Baldrick’s Foundation; *Sunesis HCT and brentuximab vedotin failure. In such very-high-risk Pharmaceuticals, Inc.; Swedish Orphan Biovitrum, Inc.; Takeda patients, PD-1 blockade is also an important salvage option. Oncology; Telomere Diagnostics, Inc.; and University of Minne- ALthough PD-1 inhibitors have undoubtedly shown remark- sota. Asterisk denotes Corporate Members. The views able activity in cHL, unfortunately in high-risk subsets of expressed in this article do not reflect the official policy or patients failing both an autologous HCT and brentuximab position of the National Institutes of Health, the Department of vedotin, the results of PD-1 blockade are modest, with a the Navy, the Department of Defense, Health Resources median duration of response in the range of 7.8 to 11.9 months and Services Administration, or any other agency of the U.S. [26,27]. This obviously is suboptimal for relapsed/refractory Government. cHL patients (with a median age in the early 30s in most pub- Financial disclosure: Supported by the CIBMTR. lished data). Considering these data, it is important to recog- Conflict of interest statement: There are no conflicts of inter- nize that allo-HCT remains an integral option in the est to report. management and cure of relapsed cHL. Authorship statement: S.A. and J.A.K. are cofirst authors. In this series we did not include myeloablative conditioning Conception and design: S.A., J.A.K., and M.H. Collection and because only a small number of cHL patients in the CIBMTR assembly of data: C.L. and M.H. Data analysis: K.W.A., C.L., and registry received haplo grafts with myeloablative conditioning M.H. First draft prepared by S.A., J.A.K., and M.H. All authors (n = 19). This analysis has the limitations that are fundamen- interpreted the data, helped revise the manuscript, and tally associated with registry-based studies, and although we approved the final version. performed a careful comparison adjusting for factors associ- ated with transplant outcomes, differences that could likely SUPPLEMENTARY MATERIALS affect our results are not readily identifiable. The higher NRM Supplementary material associated with this article can be in the haplo group may be associated with infections; how- found in the online version at doi:10.1016/j.bbmt.2019.05.025. ever, we do not have data on immune reconstitution, a limita- tion of our analysis. A higher percentage of patients in the REFERENCES MSD/CNI group had a prior autologous transplant, which may 1. Martinez C, Canals C, Sarina B, et al. Identification of prognostic factors infer a more aggressive disease pattern, partially explaining predicting outcome in Hodgkin's lymphoma patients relapsing after autol- the higher relapse rate in that group. The nature of data cap- ogous stem cell transplantation. Ann Oncol. 2013;24:2430–2434. tured in the registry does not allow us to adequately assess 2. Mariotti J, Devillier R, Bramanti S, et al. 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